The physiological role of the renin-angiotensin system is to regulate blood pressure and to maintain sodium and volume homeostasis. The key events in this system are the conversion of the polypeptide angiotensinogen to the decapeptide angiotensin I (AI) and the subsequent cleavage of the latter to give the octapeptide angiotensin II (AII). The latter peptide is a potent vasoconstrictor and a potentiator of aldosterone release. Due to potent pressor effects, AII plays a significant role in hypertension and as such has been the target for the development of antihypertensive agents.
One approach to finding such agents is to search for potent inhibitors of the angiotensin converting enzyme. Inter alia, the latter enzyme catalyzes the conversion of AI to AII. This approach has met with success and a number of such agents are used therapeutically to treat hypertension. Another approach is to find specific inhibitors of renin, an aspartyl protease which cleaves angiotensinogen to AI. Since angiotensinogen is the only known substrate for renin, this approach has the desirable feature of being aimed at a potential antihypertensive agent with a single mode of action.
The ability of renin inhibitors to lower blood pressure and to reduce plasma renin activity has been demonstrated in the clinic. For a recent review on renin inhibitors, see W. J. Greenlee, Medical Research Reviews, 10, 173 (1990). Nevertheless, progress toward obtaining the ideal renin inhibitor continues to be plagued with problems of low oral absorption, limited bioavailability and rapid elimination, mainly due to the peptidic nature of the inhibitors presently under investigation. Hence, there is a need for a readily administered, effective renin inhibitor.
The renin inhibitors of the present application can be distinguished by their non-peptidic character. The compounds are characterized by being polyhydroxylic, by having only one amide bond and a relatively low molecular weight. These features contribute to the relative stability and absorption of the inhibitors.
The following references exemplify past efforts that have been made in the search for renin inhibitors with improved characteristics:
J. R. Luly et al., U.S. Pat. No. 4,845,079, issued Jul. 4, 1989, PA1 A. K. L. Fung et al., PCT patent application WO 88/05050, published Jul. 14, 1988, PA1 H. H. Stein et al., European patent application 311012, published Apr. 12, 1989, PA1 A. K. L. Fung et al., European patent application 364804, published Apr. 25, 1990, PA1 G. J. Hanson et al., Biocheb. Biophys. Res. Commun., 146, 959 (1987), PA1 G. J. Hanson et al., Biocheb. Biophys. Res. Commun., 160, 1 (1989), PA1 D. J. Kebpf et al., J. Med. Chem., 33, 371 (1990), and PA1 D. J. Kebpf and S. L. Condon, J. Org. Chem., 55, 1390 (1990). PA1 R.sup.1 is lower alkyl; lower alkyl monosubstituted with hydroxy, lower alkoxy or benzyloxy; lower cycloalkyl; phenyl; phenyl monosubstituted with hydroxy, lower alkyl, lower alkoxy or halo; 1-naphthyl; or 2-naphthyl; PA1 R.sup.2 is lower alkyl; lower alkyl monosubstituted with hydroxy, lower alkoxy or benzyloxy; (lower cycloalkyl)methyl; benzyl; 4-imidazolylmethyl; 2-thienylmethyl; 2-thiazolylmethyl; 4-thiazolylmethyl; 2-methyl-4-thiazolylmethyl; or 2-amino-4-thiazolylmethyl; PA1 R.sup.3 is lower alkyl; (lower cycloalkyl)methyl; benzyl; or benzyl monosubstituted on the aromatic portion thereof with hydroxy, lower alkyl or lower alkoxy; PA1 R.sup.4 is lower alkyl or lower cycloalkyl; PA1 X and Y each is hydroxy and Z is hydrogen, or X and Z each is hydroxy and Y is hydrogen; with the provisos that (a) the carbon atom bearing R.sup.2 has the (R) configuration, except when R.sup.2 is 2-thienylmethyl or 2-thiazolylmethyl, X and Y each is hydroxy and Z is hydrogen, then the carbon atom bearing R.sup.2 has the (S) configuration; (b) the carbon atoms bearing R.sup.3 and R.sup.4 each has the (S) configuration; and (c) the carbon atom located between the latter two carbon atoms has the (R) configuration.